Many heart conditions require surgical repair, for example severe coronary heart disease, aneurysms of the heart, aorta or vena cava, coarctations (narrowings) of the aorta, heart valve abnormalities, arrhythmias, cardiac tumors, cardiac or great vessel trauma, and the like, can all necessitate surgery where cardiopulmonary bypass is performed. In infants and children congenital heart problems such as septal defects, trilogy or tetralogy of Fallot, and the like can similarly require bypass surgery.
For example, about one-third of all deaths occurring in affluent American and Western European societies are due to coronary artery disease. Moreover, almost all elderly people have some impairment of coronary artery circulation. While nonsurgical procedures are employed for less severe cases of coronary artery disease, surgery requiring cardiopulmonary bypass, e.g. aortic-coronary bypass surgery, frequently becomes necessary in the more severe cases.
The decision to perform surgery involving cardiopulmonary bypass is not made lightly since such surgical procedures have an approximate 4% to 5% mortality rate. Moreover, of the patients surviving such surgery, at least 10% experience complications.
To minimize the damage to cardiac tissue during bypass surgery surgeons frequently maintain the heart at cold temperatures and perfuse the heart with cardioplegic solutions to stop the heart from beating. Such an arrested heart is amenable to surgical manipulation, requires less oxygen and survives longer than an intermittently beating heart. However, improved procedures are obviously needed to reduce the mortality and morbidity rates of surgical procedures requiring cardiopulmonary bypass.
The present invention provides methods of improving recovery after bypass surgical procedures which require hypothermic cardioplegic arrest of the heart. The present methods include providing a therapeutically effective amount of a zinc-ligand conjugate in a cardioplegic solution used for cardioplegic arrest. While standardized cardioplegic solutions are available, such solutions do not contain added zinc.
Zinc has been characterized as an anti-oxidant and is thought to inhibit the mixed-function oxidase system, to inhibit liver tissue injury caused by lipid peroxidation, and to ameliorate chronic isoproternol induced heart injury and catecholamine-induced cardiomyopathy (Jeffery, 1983 Molec. Pharm. 23: 4467-473; Chvapil et al. 1973, Exp. Molec. Path. 19: 186-196; Chvapil et al. 1977 J. Molec. Cell. Card. 9: 151-159; and Singal et al. 1982 Can. J. Physiol. Pharmacol. 60: 1390-1397). Moreover, at physiological temperatures zinc has been shown to prevent arrhythmias and to improve heart function when administered during or after experimentally induced ischemia in isolated rat hearts (Powell et al. 1990 Free Radical Biol. & Med. 8: 33-46; Powell et al. 1992 FASEB J. 6 (5 Part I) Abst. No. 1799).
In a surprising departure from these prior art teachings the present inventors have discovered that administration of a zinc-ligand conjugate with cold incubation at the onset of cardioplegia provides an unexpected improvement in heart recovery from surgery. For example, the present methods can improve post-cardioplegic systolic pressure development, post-cardioplegic contractility and post-cardioplegic left ventricular relaxation in patients subjected to surgery requiring cardiopulmonary bypass.
The prior art teaches that zinc transport into endothelial cells is a facilitated process which is inhibited at cold temperatures (Bobilya et al. 1992 J. Cell. Physiol. 151: 1-7). Accordingly, the skilled artisan would not be motivated to administer zinc to hypothermic tissues. However, the present inventors have discovered that hypothermic cardioplegic heart tissues exhibit improved recovery of function when exposed to only low dosages of zinc, particularly when the zinc is administered at the onset of cardioplegia.